Vardenafil (the active ingredient of levitra), which has a structure shown by the following formula:
and a chemical name of 2-[2-ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl)phenyl]-5-methyl-7-propyl-imidazo[5,1-f][1,2,4]triazin-4-one, is a PDE5 selective inhibitor developed by Bayer Company (German) in 2001 to treat erectile dysfunction (ED) clinically.
International patent application WO 9924433 A1 first disclosed the above compound, its preparation method and uses thereof for treating ED. According to the process described in the above patent document, the last several reaction steps may be shown by the following scheme:

In the preparation method, in the late stage of preparation procedure, compound i was reacted with a high active agent, chlorosulfonic acid, to provide a water-sensitive chloro-sulfonated product ii, which was then reacted with an organic amine such as N-ethylpiperazine to give the target compound of formula I. However, it is difficult to achieve the industrialized production of the above compound by the above reaction routine. In the last stage of forming the product, the chloro-sulfonation needs consuming a large amount of chlorosulfonic acid, which prolongs the posttreatment time of the reaction, and in turn increases the amount of the impurity iii generated by the hydrolysis of the unstable intermediate (chloro-sulfonated product ii). The above hydrolysis is shown as follows:
Therefore, it needs to increase the purification time of the final product so as to meet the request for the quality of a pharmaceutical acceptable active ingredient. Therefore, in the last stage of the preparation procedure of the above process, the chloro-sulfonation not only decreases the final yield of the aimed product, but also increases the purification time of the aimed product.
International patent application WO 200250076 provided a modification to the above process so as to be more suitable for a large scale manufacture. The key steps of the modified process are shown as follows:
The process introduced a sulfonic acid group into the benzene ring by using concentrated sulfuric acid to obtain the compound iii, which was then converted into the chloro-sulfonated product ii by using thionyl chloride. The replacement of chlorosulfonic acid used in the original process with thionyl chloride increased the yield of the reaction, facilitating the production of the product. But similar to WO 9924433 A1, this process obtained the aimed product by reacting the chloro-sulfonated product ii, which is highly sensitive to water, with N-ethylpiperazine. Thus, during processing, it exists inevitably the side reaction wherein the generated intermediate ii is re-hydrolyzed to the impurity iii.
Although WO 200250075 and US 2006264624 sequentially disclosed new intermediates for vardenafil, and new preparation methods thereof, the above technical problem is not thoroughly solved. In the methods for preparing vardenafil reported in Journal of Organic Chemistry, 2005, 70(18): 7331-7337; organic Process Research & Development, 2005, 9(1), 88-97; and Chemical Agent, 2006, 28(5), 287-288, the above technical problem is also discussed.